The potency and safety of TRAIL has prompted clinical trials with the recombinant protein as a novel treatment for human cancer. While TRAIL is very active in killing tumor cells, recombinant TRAIL possesses drug properties that limit its efficacy such as short serum half-life, instability, and the inability to cross the intact blood-brin barrier. To overcome these limitations we identified a small molecule inducer of the TRAIL gene, TIC10 that is superior to recombinant TRAIL in terms of stability, bioavailability, ability to cros the blood-brain barrier, cost of production, and spectrum of activity. Importantly, our data shows that TIC10 is highly active in several aggressive and therapy-resistant cancers. On a mechanistic level, TIC10 causes potent antitumor effects and TRAIL-induction that is mediated by the transcription factor Foxo3a, which directly regulates the TRAIL gene promoter. Furthermore, we found that TIC10 results in the dual inactivation of Akt and ERK, thereby inhibiting their constitutive phosphorylation of Fox3a and potentiating its translocation to the nucleus and binding to the TRAIL gene promoter (Allen et al, Science Translational Medicine, In Press, 2013). We hypothesize that TIC10 induces potent antitumor effects that require Akt- and ERK-mediated Foxo3a nuclear translocation and transcriptional activation of the TRAIL gene. To address the hypothesis we propose the following specific aims:
Specific Aim #1 : Identify TIC10-induced effects on Foxo3a expression, phosphorylation, and subcellular localization;
Specific Aim #2 : Elucidate the role of Akt and ERK kinases in the mechanism of action of TIC10;
Specific Aim #3 : Determine the differential regulation of TRAIL gene transcription by FOXO family members. These studies will create a comprehensive molecular understanding of how TIC10 harnesses Foxo3a to achieve its potent antitumor activity and also has the potential to undercover novel regulatory mechanisms of Foxo3a activity that are biologically significant. Preclinical cancer models including orthotopic xenografts and transgenic mice along with primary human tumor specimens will substantiate the efficacy and validate the mechanistic findings regarding TIC10 and Foxo3a. Together, these studies will elucidate key and novel regulatory mechanisms involving Foxo3a with the first-in-class molecule TIC10 to yield insight regarding its mechanism of action as well as in clinical samples in the context of colon cancer disease progression. Our studies will facilitate the clinical translation of a novel anti-cancer therapeutic agent through further development in preclinical laboratory studies.

Public Health Relevance

We have discovered a new drug called TIC10 that uses normal and cancer cells to make a substance in your body called TRAIL that kills cancer cells. The compound is active in treating many different types of tumors, including brain tumors that are very difficult to treat. These studies will help understand how TIC10 works, will identify how key cell signaling molecules are changed by TIC10, and see if similar changes are seen in actual tumors of patients. This work will help greatly to advance TIC10 to the clinic in the future

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
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Kondapaka, Sudhir B
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Pennsylvania State University
Internal Medicine/Medicine
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Wagner, Jessica; Kline, C Leah; Zhou, Lanlan et al. (2018) Anti-tumor effects of ONC201 in combination with VEGF-inhibitors significantly impacts colorectal cancer growth and survival in vivo through complementary non-overlapping mechanisms. J Exp Clin Cancer Res 37:11
Lev, Avital; Lulla, Amriti R; Ross, Brian C et al. (2018) ONC201 Targets AR and AR-V7 Signaling, Reduces PSA, and Synergizes with Everolimus in Prostate Cancer. Mol Cancer Res 16:754-766
Wagner, Jessica; Kline, C Leah; Zhou, Lanlan et al. (2018) Dose intensification of TRAIL-inducing ONC201 inhibits metastasis and promotes intratumoral NK cell recruitment. J Clin Invest 128:2325-2338
Kline, Christina Leah B; Ralff, Marie D; Lulla, Amriti R et al. (2018) Role of Dopamine Receptors in the Anticancer Activity of ONC201. Neoplasia 20:80-91
Ralff, Marie D; Kline, Christina L B; Küçükkase, Ozan C et al. (2017) ONC201 Demonstrates Antitumor Effects in Both Triple-Negative and Non-Triple-Negative Breast Cancers through TRAIL-Dependent and TRAIL-Independent Mechanisms. Mol Cancer Ther 16:1290-1298
Ralff, Marie D; Lulla, Amriti R; Wagner, Jessica et al. (2017) ONC201: a new treatment option being tested clinically for recurrent glioblastoma. Transl Cancer Res 6:S1239-S1243
Lev, Avital; Lulla, Amriti R; Wagner, Jessica et al. (2017) Anti-pancreatic cancer activity of ONC212 involves the unfolded protein response (UPR) and is reduced by IGF1-R and GRP78/BIP. Oncotarget 8:81776-81793
El-Deiry, Wafik S (2016) p21(WAF1) Mediates Cell-Cycle Inhibition, Relevant to Cancer Suppression and Therapy. Cancer Res 76:5189-91
Allen, Joshua E; Kline, C Leah B; Prabhu, Varun V et al. (2016) Discovery and clinical introduction of first-in-class imipridone ONC201. Oncotarget 7:74380-74392
Kline, C Leah B; Van den Heuvel, A Pieter J; Allen, Joshua E et al. (2016) ONC201 kills solid tumor cells by triggering an integrated stress response dependent on ATF4 activation by specific eIF2? kinases. Sci Signal 9:ra18

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